1. Field of the Invention
The present invention relates to the prevention or treatment of type 2 diabetes mellitus (T2DM) and reduction of blood glucose levels. More specifically it relates to serial administration of two complementary compositions that effectively reduce glucose levels in the blood of mammals, including humans. The first composition (Comp1) potentiates mammalian physiological and pharmacological responses to the second composition (Comp2) which includes hypoglycemic agents.
2. Description of the Related Art
The prevalence of diabetes is increasing in developed countries and in developing countries, as they become more affluent. Sixteen million Americans have diabetes with an additional 798,000 new cases appearing annually. T2DM represents 80% of all diabetes in the USA and is increasing more rapidly in some ethnic groups (http://www.wrongdiagnosis.com/d/diab2/basics.htm; http://www.5mcc.com/Assets/SUMMARY/TP0264.html). The incidence of T2DM in non-Hispanic whites increased 300% in the decade between 1987 and 1996 (Burke J P et al. Arch Intern Med. 1999, 159:1450-1456). In Australia the prevalence of diabetes is estimated at 7.4% of the population whereas the prevalence of people exhibiting abnormal glucoses levels, and therefore at risk of developing diabetes, is 16.4%. In the latter group, there is a marked increase with increasing age: 37% of those aged 55-64 years, 47% of those aged 65-74 years, and 53% of those aged 75 years and above. The prevalence of diabetes in Australia has more than doubled since 1981 and it is expected that 1.23 million Australians will suffer from diabetes in 2010 (Dunstan D W, Diabetes Care 2002, 25:829-834; http://www.healthinsite.gov.au/content/internal/page.cfm?ObjIb=00001FB3-0318-1D2D-81CF83032BFA006D). Approximately 1 in 4 Australians aged 25 years and older has a condition of impaired glucose metabolism or clinical diabetes. The Australian and American government health regulatory agencies have stated that diabetes is one of the top health priorities (http://www.healthinsite. gov.au/content/internal/page.cfm?ObjID=00001FB3-0318-1D2D-81CF83032BFA006D). The combined population suffering from type 1 and type 2 diabetes mellitus (T1DM and T2DM) in seven major world markets is projected to grow from 39.4 million to 49.4 million from 2003 to 2010, an estimated growth rate of 25.4% (http://www.ims-global.com/insight/news_story/0206/news_story—020611.htm).
T2DM causes numerous complications such as cardiovascular disease, stroke, blindness, nerve and renal damage and inflammatory disorders. In both human and economic terms, diabetes is one of the most costly diseases in the world. The American Diabetes Association (ADA) estimates that the total direct cost associated with diabetes care each year in the USA is US$ 45 billion and growing (Pardes H, Science 1999, 283:36-37). Indirect costs are very difficult to measure, but a recent study in Sweden suggests that the indirect costs of treating diabetes are approximately 158% of the direct costs (Henriksson F, Pharmacoeconomics 2002, 20:43-53). Furthermore, complications arising from T2DM account for 3.5 fold increases in individual costs and 5.5 fold increases in hospitalization costs (Williams R et al. Diabeteologia 2002, 47:S13-S17).
One of the main contributing factors of diabetes and diabetes related diseases is hyperglycemia (persistent abnormal elevation in blood glucose levels). There is a clear unmet medical need for effective and safe medications to reduce abnormal blood glucose profiles and to treat and prevent diabetes and its ancillary pathology. In this regard, an extensive interest exists within clinical and research communities to develop natural products or compounds that are already present in mammals and act to reduce blood glucose levels.
Despite the number of compositions proposed to be useful for treating T2DM, the efficacy or safety of such compositions has typically not been reported. For example, the composition disclosed in U.S. Pat. No. 6,787,163 is proposed to regulate glucose levels and includes vanadyl sulfate, diethylethanolamine and copper. However, a possible relationship between vanadyl sulfate and cancer must be firmly considered. While literature indicates cytotoxicity of vanadyl sulfate to cancer cells, there are also reports of possible cancer causing activity of vanadyl sulfate related to DNA damage (Wozniak K, Arch Toxicol. 2004, 78:7-15). Further, vanadium compounds have been reported to promote the induction of unwanted morphological transformation of hamster embryo cells (Rivedal E et al. Cell Biol Toxicol. 1990, 6:303-314). Exposure of humans to diethylethanolamine results in symptoms of irritation, and it contributes to the development of asthma in some (0.6%) individuals (Gadon M. E. et al. J Occup Med. 1994, 36(6):623-6). Administration of 100 ppm diethylethanolamine vapor to timed-pregnant Sprague-Dawley rats for 6 hours a day results in dry rales, statistically significant reduction of body weight (by 9.5%), and reduction of weight gain (by 48%) during exposure (Leung H W et al. J Appl Toxicol. 1998, 18:191-196). Nasal cavities of rats exposed to 25 or 76 ppm of diethylethanolamine for 14 weeks revealed evidence of inflammatory cell infiltration, focal hyperplasia, and squamous metaplasia in the respiratory epithelium of the anterior nasal turbinate (Hinz J P et al. Fundam Appl Toxicol. 1992, 18(3):418-24). Copper is increased in T2DM patients and promotes heart failure. Copper chelation increases the level of copper in urine, improves copper excretion, reduces blood levels of copper, results in the alleviation of heart failure, improves cardiomyocyte structure, and is effective in the reversal of left ventricular hypertrophy and collagen and beta(1) integrin deposition (Cooper G J et al. Diabetes. 2004, 53:2501-2508; US Patent Publication 20030203973A1). Therefore, copper is expected to aggravate diabetes and its ancillary pathology.
Accordingly, there is a need in the art for methods and compositions to reduce and stabilize blood glucose levels.